The long-term objective of this project is to understand how age-related changes in the lens proteins contribute to cataract. The proposed research will examine the composition and structure of light scattering protein aggregates and water-insoluble protein that form in aged human lenses using mass spectrometry. The specific aims of the project are to: 1) quantify the protein composition of protein aggregates and water-insoluble protein in normal and cataractous human lenses;2) identify sites in aggregated and water-insoluble lens proteins that form intermolecular disulfide cross-links during aging, and 3) map the contact sites occurring in aggregated and water-insoluble lens proteins using chemical cross-linkers. The results will provide new information about the structure of light scattering proteins in human lens so that the mechanism of age-related protein aggregation and insolubilization can be eventually deduced. This information may lead to therapeutic strategies to slow the rate of age-related cataract formation by inhibiting protein aggregation. The research is important to human health, because cataracts are a major human disease for which there is no useful treatment other than surgical extraction of the lens. PUBLIC HEALTH RELEVANCE: Age-related cataracts are a major health problem caused by aggregation and light scatter of lens proteins. This study will use mass spectrometry to analyze the composition and structure of protein aggregates in human lens. The results may suggest therapies to slow cataract formation by inhibiting protein aggregation in the aged lens.